Cellular Differentiation

More than 50 years ago, Conrad Waddington illustrated the normal embryonic development by his epigenetic landscape (Figure 1; (Waddington, 1957)). It compares the various developmental pathways a cell takes during the process of differentiation to a ball rolling down a series of ridges and valleys. The epigenetic landscape visually displays the natural constraints of cell differentiation potential during development (Figure 1 and 2). Transcription factors orchestrate this developmental process within each cell. A series of landmark experiments, however, showed that the cell fate decisions are flexible and can be reversed (Jopling et al., 2011). Recent advances have shown that the cells can lose potency and revert to pluripotency (reprogramming) and also switch lineages (dedifferentiation and transdifferentiation) (Jopling et al., 2011).

Dedifferentiation: Here, a terminally differentiated cell reverts back to a less-differentiated state without switching lineages. Several non-mammalian vertebrate species can regenerate involving dedifferentiation of mature cells. Some examples of natural dedifferentiation include: (i) natural dedifferentiation during heart regeneration in zebrafish (Poss et al., 2002); (ii) dedifferentiation during limb regeneration in urodele amphibians (Burkhart and Sage, 2008); (iii) dedifferentiation of associated Schwann cells upon nerve damage in mammals (Chen et al., 2007; Mirsky et al., 2008). Also, experimental induction of dedifferentiation has been done in vitro and in vivo to promote regeneration in mammalian tissues otherwise lacking this ability. Examples of experimental dedifferentiation include: (i) promoting muscle cells to differentiate by treating mouse myotubes either by treating them with extracts from regenerating newt limbs or through inactivation of retinoblastoma protein (RB) and tumor suppressor alternate reading frame (ARF) (Jopling et al., 2011; McGann et al., 2001); (ii) dedifferentiation and enhanced proliferation of mature cardiomyocytes occurs in mice lacking both RB and RB-like 2 (RBL2) or through combined FGF1 stimulation and p38 MAPK inhibition or by treatment with Neuregulin (Jopling et al., 2011; Rumyantsev, 1977).

Transdifferentiation: Here, the cells revert to a stage where they can swtich lineages and differentiate into a new cell type. Natural transdifferentiation can occur through dedifferentiation of a cell and differentiation into a new lineage. Example includes newt lens regeneration (Tsonis et al., 2004). Following lens removal, RB is inactivated followed by upregulation of cancer and apoptosis-related genes together with histone deacetylases and histone demethylases (Jopling et al., 2011; Tsonis et al., 2004). Experimental induction of transdifferentiation have also been performed by direct conversion of one cell type to the other by modulating their genetic programs. Examples include: B cells to macrophages by using the transcription factors CCAAT-enhancer-binding protein-α (CEBPα) and CEBPβ (Xie et al., 2004); hepatocyte to pancreatic cell transdifferentiation by overexpression of Pancreas and duodenum homeobox 1 (PDX1) (Meivar-Levy et al., 2007); fibroblasts to neuronal transdifferentiation with transcription factor achaete–scute homologue 1 (ASCL1) (Vierbuchen et al., 2010); fibroblasts to cardiomyocytes with GATA4, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5) (Ieda et al., 2010).

References:

1. Burkhart, D.L., Sage, J., 2008. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8, 671-682.

2. Chen, Z.L., Yu, W.M., Strickland, S., 2007. Peripheral regeneration. Annu Rev Neurosci 30, 209-233.

3. Ieda, M., Fu, J.D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B.G., Srivastava, D., 2010. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375-386.

4. Jopling, C., Boue, S., Izpisua Belmonte, J.C., 2011. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 12, 79-89.

5. McGann, C.J., Odelberg, S.J., Keating, M.T., 2001. Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc Natl Acad Sci U S A 98, 13699-13704.

6. Meivar-Levy, I., Sapir, T., Gefen-Halevi, S., Aviv, V., Barshack, I., Onaca, N., Mor, E., Ferber, S., 2007. Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein beta. Hepatology 46, 898-905.

7. Mirsky, R., Woodhoo, A., Parkinson, D.B., Arthur-Farraj, P., Bhaskaran, A., Jessen, K.R., 2008. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J Peripher Nerv Syst 13, 122-135.

8. Poss, K.D., Wilson, L.G., Keating, M.T., 2002. Heart regeneration in zebrafish. Science 298, 2188-2190.

9. Rumyantsev, P.P., 1977. Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol 51, 186-273.

10. Tsonis, P.A., Madhavan, M., Tancous, E.E., Del Rio-Tsonis, K., 2004. A newt's eye view of lens regeneration. Int J Dev Biol 48, 975-980.

11. Vierbuchen, T., Ostermeier, A., Pang, Z.P., Kokubu, Y., Sudhof, T.C., Wernig, M., 2010. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041.

12. Waddington, H.K., 1957. Fetal salvage in abruptio placentae. Am J Obstet Gynecol 73, 816-821.

13. Xie, H., Ye, M., Feng, R., Graf, T., 2004. Stepwise reprogramming of B cells into macrophages. Cell 117, 663-676.